9GPQ

The FK1 domain of FKBP51 in complex with the macrocyclic SAFit analog 12h/p

これはPDB形式変換不可エントリーです。

9GPQ の概要

• エントリーDOI: 10.2210/pdb9gpq/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, 3-cyclohexyl-19,20-dimethoxy-17-methyl-11,18-dioxa-1,17lambda5-diphospha-19lambda5-stannapentacyclo[17.3.1.04,9.04,13.015,20]tricosane-2,10-quinone (3 entities in total)
• 機能のキーワード: fkbp, inhibitor, safit, macrocycle, complex, isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29173.51

構造登録者

Meyners, C.,Buffa, V.,Walz, C.,Hausch, F. (登録日: 2024-09-09, 公開日: 2025-01-15, 最終更新日: 2025-03-19)

主引用文献

Buffa, V.,Walz, C.,Meyners, C.,Zheng, M.,Oki Sugiarto, W.,Repity, M.,Achaq, H.,Brudy, C.,Spiske, M.,Cica, M.,Hausch, F.
Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles.
Angew.Chem.Int.Ed.Engl., 64:e202418512-e202418512, 2025

PubMed Abstract: Macrocycles are abundantly used by nature to enable cell-permeable bioactive molecules. Synthetic non-peptidic macrocycles are also increasingly considered as modalities for difficult-to-bind proteins but guidelines for macrocyclization are only beginning to emerge. Macrocycles are thought to constrain the available conformations but also to allow for residual flexibility, the latter being poorly understood. Here we show that even medium-sized macrocycles display an unexpected high conformational plasticity, even when bound to their protein target. Minor modification of the linker region of macrocycles can shift the conformational ensemble to distinct conformational subclasses, each constituting distinct three-dimensional scaffolds for further optimization. This led to several new ligands with improved affinity and beneficial physicochemical parameters for the FK506-binding protein 51, a promising target for depression, obesity and chronic pain. Importantly, none of the beneficial modifications could have been identified by classical medicinal chemistry as they only work in the macrocyclic context. Our results show that macrocyclization can do more than keeping loose ends together but rather provide a platform for multiple series of macrocycles with distinct binding modes.

PubMed: 39749563
DOI: 10.1002/anie.202418512

実験手法

X-RAY DIFFRACTION (1.35 Å)